Zang Yong, Lee J Jack, Yuan Ying
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Clin Trials. 2014 Jun;11(3):319-327. doi: 10.1177/1740774514529848.
Background Traditionally, the purpose of a dose-finding design in cancer is to find the maximum tolerated dose based solely on toxicity. However, for molecularly targeted agents, little toxicity may arise within the therapeutic dose range and the dose-response curves may not be monotonic. This challenges the principle that more is better, which is widely accepted for conventional chemotherapy. Methods We propose three adaptive dose-finding designs for trials evaluating molecularly targeted agents, for which the dose-response curves are unimodal or plateaued. The goal of these designs is to find the optimal biological dose, which is defined as the lowest dose with the highest rate of efficacy while safe. The first proposed design is parametric and assumes a logistic dose-efficacy curve for dose finding, the second design is nonparametric and uses the isotonic regression to identify the optimal biological dose, and the third design has the spirit of a 'semiparametric' approach by assuming a logistic model only locally around the current dose. Results We conducted extensive simulation studies to investigate the operating characteristics of the proposed designs. Simulation studies show that the nonparametric and semiparametric designs have good operating characteristics for finding the optimal biological dose. Limitations The proposed designs assume a binary endpoint. Extension of the proposed designs to ordinal and time-to-event endpoints is worth further investigation. Conclusion Among the three proposed designs, the nonparametric and semiparametric designs yield consistently good operating characteristics and thus are recommended for practical use. The software to implement these two designs is available for free download at http://odin.mdacc.tmc.edu/~yyuan/ .
背景 传统上，癌症剂量探索设计的目的是仅基于毒性来找到最大耐受剂量。然而，对于分子靶向药物，在治疗剂量范围内可能几乎没有毒性，且剂量反应曲线可能不是单调的。这对“越多越好”这一传统化疗中被广泛接受的原则提出了挑战。方法 我们为评估分子靶向药物的试验提出了三种适应性剂量探索设计，这些药物的剂量反应曲线是单峰或平台型的。这些设计的目标是找到最佳生物学剂量，其定义为在安全的同时具有最高疗效率的最低剂量。提出的第一种设计是参数化的，在剂量探索时假设为逻辑剂量-疗效曲线，第二种设计是非参数化的，使用等渗回归来确定最佳生物学剂量，第三种设计具有“半参数化”方法的特点，仅在当前剂量附近局部假设逻辑模型。结果 我们进行了广泛的模拟研究来考察所提出设计的操作特性。模拟研究表明，非参数化和半参数化设计在寻找最佳生物学剂量方面具有良好的操作特性。局限性 所提出的设计假设为二元终点。将所提出的设计扩展到有序和事件发生时间终点值得进一步研究。结论 在提出的三种设计中，非参数化和半参数化设计始终具有良好的操作特性，因此推荐实际使用。实现这两种设计的软件可在http://odin.mdacc.tmc.edu/~yyuan/免费下载。
